This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Overview: The overall goal of this project is to develop new pulse sequences and methods for quantitative structural and perfusion MRI in support of research projects and clinical applications of the Resource Center, which focuses on imaging of neurodegenerative diseases. Most neurodegenerative diseases are associated with subtle and slowly progressing alterations in the brain that are often difficult to detect with MRI. A major focus of this project is the development of improved structural MRI methods that provide enhanced tissue contrast for more precise measurements of brain tissue degeneration and loss, such as regional cortical thinning. Another major focus is the development of better methods for quantification of brain perfusion as a means to determine brain physiology and function in neurodegenerative conditions. Aim 1: The aim is to develop concepts of variable contrast-weighted imaging (VTI) for the enhancement of spatial resolution in structural MRI. The vast majority of structural MRI studies of the brain rely on T1 or/and T2 weighting for image contrast. However, the accurate representation of brain tissue boundaries based on T1 and T2 alone has limitations, because the relaxation properties of gray matter and white matter partially overlap. To overcome these limitations, aim 1 focuses on multi-acquisition variable T1-weighted imaging in conjunction with T1 estimations by least-squares fits with spatial priors to improve image contrast and accuracy in delineating tissue boundaries. Aim 2: The aim is to develop methods for better quantification of cerebral blood flow and estimations of water transfer into the brain based on arterial spin labeling (ASL) MRI. In particular, the objective is to evaluate variations in both T1 and T2 relaxation of the ASL signal to characterize brain physiology and function as reflected by water transfer into the brain. Toward this goal, the aim will focus on modeling perfusion dynamics in dual-echo 3D GRASE data, as developed in project 2 that provide intrinsic measures of T1 and T2 relaxation of the ASL signal. Aim 3: Although it is expected that specific aim 1 will provide improved image contrast at tissue boundaries through variable T1 weighting, white matter areas will remain largely featureless. Moreover, the precision in delineating brain tissue boundaries based on T1 alone could be limited because gray matter and white matter partially overlap in their T1 characteristics. We therefore propose a generalization of aim 1 by adding diffusion weighting to high-resolution structural MRI, complementing the T1 contrast. Specifically, the new aim 3 is designed to 1) develop high resolution structural MRI with joined T1 and diffusion weighting for improved measurements of boundaries and surfaces of brain structures and 2) extend diffusion weighting by diffusion correlation weighting that imprints a new diffusion contrast on high resolution MRI. Toward these goals, high resolution MPRAGE with spiral k-space readout will be developed as part of a subcontract described in high resolution spiral MPRAGE, by Dr. Matthias Guenther.